Estrogens

Question 1

What is the change in estrogen and progesterone levels during the menstrual cycle?

Answer 1

Early Follicular:
Estrogen -> suppresses FSH production
Late Follicular:
Estrogen -> stimulates surge of LH and FSH (ovulation & formation of corpus luteum)
Luteal:
Estrogen + Progesterone -> suppress production of LH and FSH

Question 2

What are the physiological effects of estrogens? (5)

Answer 2

1) female maturation
- development of vagina, uterus
- stromal development
- accelerated growth
- hair growth
- alteration in body fat distribution
- pigmentation changes
2) endometrial effects
- development of endometrial lining during menstrual cycles
- prolonged exposure leads to hyperplasia of endometrium and abnormal bleeding
3) metabolic + cardiovasc effects
- osteoporosis
- stim of SHBG
- alteration in HDL/LDL
4) blood coagulation
5) CNS (mood)

Question 3

What is the consequence of the enterohepatic circulation in estrogen metabolism?

Answer 3

Estrogen is reused which prolongs its action and increases overall hormone levels

Question 4

What are the clinical uses of estrogens? (4)

Answer 4

1) hormone replacement therapy in postmenopausal women
- relief of CNS disturbances
- relief of sx from urogenital atrophy
- relief of psychological effects
2) osteoporosis
- post menopausal only
- estrogens decrease rate of bone resorption
3) hormonal contraceptive
4) replacement therapy in pt with hypogonadism
- ovary development failure
- chromosomal disorder
- castration

Question 5

What are the adverse effects of estrogens? (4)

Answer 5

1) uterine bleeding
- estrogen therapy is major cause
- endometrial hyperplasia
- can be prevented with admin of progestin
2) endometrial carcinoma
- use with progestin to reduce risk
3) breast cancer
- long term use
- addition of progestin will not protect
4) nausea/headache/fluid retention/weight gain

Question 6

What structural characteristics are responsible for variance in drug properties in steroidal and non-steroidal estrogens?

Answer 6

• 16-OH decreases activity
• 17a-ethynyl substituent blocks metabolism and allows for oral activity
• 17B OH group required for activity, can be temporarily blocked by ester for drug delivery
• hydroxyl at 3 is essential for activity
• aromaticity in ring is required
• ether is readily hydrolyzed in vivo

Question 7

What is the MOA of SERMs?

Answer 7

-partial estrogen agonists (blocking action of strong estrogens) in some tissues
mostly nonsteroidal
(ex) Tamoxifen, Raloxifene

Question 8

17a-alkylated estrogens (3)

Answer 8

• this alkylation prevents conversion to estrone (enhancing oral bioavailability and increases HF)
• 3-alkylated ether is quickly
  dealkylated in vivo
  (ex) Mestranol, Quinestrol, Ethinyl estradiol

Question 9

What are the pharmacological uses of aromatase inhibitors? (4)

Answer 9

• blocks biosynthesis of estrogens
• effective in pt whose breast cancer is resistant to tamoxifen
• ovulation induction (off label)
• gynecomastia

Question 10

What is the MOA of estrogen antagonists?

Answer 10

blocks estrogen in all tissues
(ex) Fulvestrant

Question 11

Fulvestrant (SERD)

Answer 11

• pure estrogen receptor antagonist for treatment of breast cancer
• somewhat more effective than SERM in pt who are resistant to tamoxifen

Question 12

Non-steroidal estrogens (2)

Answer 12

1) Diethylstilbestol
- prevent miscarriage
- inc risk of vaginal adenocarcinoma in women exposed in utero
- used in advanced prostate cancer
2) Chlorotrianisene
- postpartum breast engorgement
- menopause sx
- prostate cancer

Question 13

Estrogenic esters (2)

Answer 13

ex) estradiol valerate + cypionate
- esterification decreases solubility and slots absorption
- slow absorption from injection site prolongs action

Question 14

Tamoxifen

Answer 14

SERM
- prodrug, oxidized in vivo
- partial estrogen agonist
- antiestrogen actions (breast cancer treatment)
- estrogenic actions (inc risk for thromboembolic events, prevents osteoporosis)

Question 15

Toremifene

Answer 15

SERM
- structurally similar to tamoxifen
- used to treat advanced breast cancer

Question 16

Ospemifene

Answer 16

**SERM
- structurally similar to toremifene
- estrogenic effects on vaginal epithelium
- used to treat dyspareunia in post menopausal women

Question 17

Raloxifene

Answer 17

**SERM, partial estrogen agonist
- tissue specific activity
- estrogen actions (prevents osteoporosis, dec LDL, inc risk for blood clots)
- antiestrogen actions (dec risk for breast cancer, does not stimulate endometrial cells, may cause hot flashes

Question 18

Clomiphene

Answer 18

**SERM, partial estrogen agonist
- inc secretion of FSH and LH by inhibiting negative estradiol feedback
- used to stimulate ovulation in women with oligomenorrhea/amenorrhea/ovulatory dysfunction
- polycystic ovary syndrome

Question 19

Conjugated estrogens

Answer 19

• usually collected from pregnant urine
• mixture 50-60% estrone, 20-30% equilin
  (ex) estrone sulfate, equilin sulfate

Question 20

Aromatase Inhibitors

Answer 20

(ex) Anastrazole, Letrozole, Exemestane
- block biosynthesis of estrogens
- effective in pts whose breast cancer is resistant to tamoxifen
- ovulation induction off label
- gynecomastia